5-(Optionally substituted phenyl)-6H-1,3,4-thiadiazine-2-amines

ABSTRACT

A method of inducing sedation in a patient comprises administering to a patient in which sedation is desired an amount effective for inducing sedation of a compound of the formula ##STR1## wherein R is H, or C 1-5  or 7 -straight or branched chain alkyl: 
     R 1  is H, C 1-5  or 7 -straight or branched chain alkyl or allyl; 
     R 2  is phenyl or phenyl substituted with F, Cl, Br, NO 2 , C 1-5   straight or branched chain alkyl, C 1-5  straight or branched chain alkoxy, 2,4-di-Cl, 2,4-di-F or 2,4-di-Br, with the proviso that when the phenyl group is monosubstituted with F, the F atom is not in the o-position; and 
     R 3  is H or C-1-5 straight or branched chain alkyl, with the proviso that when R 3  is straight or branched chain alkyl, R 2  is unsubstituted phenyl; or 
     a pharmaceutically acceptable acid addition salt thereof.

RELATIONSHIP TO OTHER APPLICATIONS

This application is related to copending application Ser. Nos. 071,952,071,970, 072,793 and 071,966, all filed Sept. 4, 1979.

BACKGROUND OF THE INVENTION

The present invention relates to 5-(optionally substitutedphenyl)-6H-1,3,4-thiadiazine-2-amines, having activity as sedatives.

As a general class, 5-(optionally substitutedphenyl)-6H-1,3,4-thiadiazine-2-amines are known as chemicalintermediates. See, for example, Japanese Pat. Nos. 74-110,696,74-110,697 and 74-100,080. Many individual species within the scope ofthe compounds defined herein and also species related thereto are alsoknown as chemical intermediates. See, for example:

1. Japanese Pat. No. 75 37651;

2. McLean et al, J. Chem. Soc. 1937, 556-9;

3. Avramovici, Analele stiint. univ. "Al. I. Cuza" lasi, Sect. 1 (Mat.Fiz., chim.). (N.S.) 1, 315-319 (1955). CA51:10541;

4. Beyer et al, Justus Liebigs Ann. Chem. 741, 45-54 (1970);

5. Japanese Pat. No. 74-110,696;

6. Japanese Pat. No. 74-110,697;

7. Bose, Quart. J. Indian Chem. Soc. 1, 51-62 (1924).

8. Beyer et al, Chem. Ber. 89, 107-14 (1956);

9. Japanese Pat. No. 74-88,889;

10. Japanese Pat. No. 74-100,080;

11. Bose, Quart. J. Ind. Chem. Soc. 2, 95-114 (1925).

12. Bose et al, J. Indian Chem. Soc. 7, 733-9 (1930);

13. Bulka et al, Z. Chem. 15(12), 482 (1965);

14. Schmidt et al, Tetrahedron Lett. 1975 (1), 33-6;

15. Beyer, Quart. Rep. Sulfur Chem. 5(3), 177-89 (1970);

16. Saraswathi et al, Indian J. Chem. 10(12), 1151-4 (1972);

17. Hampel, Z. Chem. 9(2), 61-2 (1969);

18. Pfeiffer et al, Z. Chem. 17(6), 218-20 (1977);

19. Pfeiffer et al, Synthesis 1977(7), 485-6; and

20. Pfeiffer et al, Synthesis 1977(3), 196-8.

Certain species are further known as flame retardants (Japanese Pat. No.74-5439).

Moreover, some 2-amino-1,3,4-thiadiazines are generally known to haveantiviral, antiinflammatory and analgesic activity (Japanese Pat. No.74-88889). Additionally, many individual species within the scope ofthose defined herein, as well as others related in structure aredisclosed in this same reference. Some species have been foundineffective as vitamin B substitutes (Robbins et al, Proc. Natl. Acad.Sci. U.S. 24, 141-5 (1938) and antitubercular agents (Ban., J. Pharm.Soc. Japan 73, 533-7 (1953) and Bilinski et al, Bull. Acad. Polon. Sci.,Ser. Sci. Chim. 13(6), 393-6 (1965)).

Other compounds having significantly different structures are also knownto possess pharmacological activity.

4-methyl-4H-5,6-dihydro-1,3,4-thiadiazin-2-amines are known to be CNSactive (U.S. Pat. No. 3,428,631 and Trepanier et al, J. Med. Chem.10(6), 1085-7 (1967)). Additionally,3-substituted-1,2-dihydro-1,3,4-thiadiazin-2-imines are known as slowcure accelerators for rubber (U.S. Pat. No. 2,871,237).

The 5-membered ring-containing 2-amino-1,3,4-thiadiazoles are known topossess CNS depressant activity (Maffii et al, Il Farmaco (Pavia) Ed.Sci. 13, 187-217 (1958); Great Britain Pat. No. 815,188; W. German Pat.No. 2,212,245 (or Great Britain Pat. No. 1,380,136); U.S. Pat. No.3,965,110; U.S. Pat. No. 4,054,665; U.S. Pat. No. 3,919,428; and U.S.Pat. No. 3,992,396) and antihypertensive activity (U.S. Pat. No.3,746,716).

These 5-membered ring-containing 1,3,4-thiadiazole-2-amines are a classof compounds treated by the prior art as distinct from the 6-memberedring-containing 1,3,4-thiadiazin-2-amines. However, the preparation ofboth types of compounds are reported together by Rao, Khim. Geterotsikl.Soedin. 1977(3), 291-310, as does Klosa, Arch. Pharm. 287, 12-14 (1954).In the latter reference, the compounds are reported as potential, butuntested, tuberculostatics. Compounds of both types are also disclosedin Japanese Pat. No. 74 5439 as fire retardants.

SUMMARY OF THE INVENTION

A method of inducing sedation in a patient comprises administering to apatient in which sedation is desired an amount effective for inducingsedation of a compound of the formula ##STR2## wherein R is H, or C₁₋₅or 7 -straight or branched chain alkyl;

R₁ is H, C₁₋₅ or 7 -straight or branched chain alkyl or allyl;

R₂ is phenyl or phenyl substituted with F, Cl, Br, NO₂, C₁₋₅ straight orbranched chain alkyl, C₁₋₅ straight or branched chain alkoxy, 2,4-di-Cl,2,4-di-F or 2,4-di-Br, with the proviso that when the phenyl group ismonosubstituted with F, the F atom is not in the o-position; and

R₃ is H or C₁₋₅ straight or branched chain alkyl, with the proviso thatwhen R₃ is straight or branched chain alkyl, R₂ is unsubstituted phenyl;or

a pharmaceutically acceptable acid addition salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

Illustrative examples of straight or branched chain C₁₋₅ alkyl groupsmentioned above in all instances in describing the groups R, R₁, R₂ andR₃ include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, etc.Illustrative examples of straight or branched chain C₇ alkyl groupswhich R and R₁ may represent as used herein include, for example,n-heptyl, isoheptyl, etc.

Illustrative examples of straight or branched chain C₁₋₅ alkoxy groupsmentioned as substituents for the R₂ phenyl group as used hereininclude, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy,etc.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include those of any suitable inorganic or organic acid.Suitable inorganic acids are, for example, hydrochloric, hydrobromic,sulfuric or phosphoric acid. Suitable organic acids are, for example,carboxylic acids, such as acetic, propionic, glycolic, lactic, pyruvic,malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic,hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,salicylic and 2-phenoxybenzoic, or sulfonic acids such as, for example,methanesulfonic and 2-hydroxyethane-sulfonic acid.

Of the compounds of Formula I, those wherein R₂ is 2,4-dichlorophenyl,especially those wherein also R₁ is C₁₋₅ straight or branched chainalkyl or allyl are preferred. Thus, preferred compounds include5-(2,4-dichlorophenyl)-N,N-dimethyl-6H-1,3,4-thiadiazin-2-amine,5-(2,4-dichlorophenyl)-N-(1-propyl)-6H-1,3,4-thiadiazin-2-amine,5-(2,4-dichlorophenyl)-N-2-propenyl-6H-1,3,4-thiadiazin-2-amine andtheir acid addition salts.

Illustrative examples of compounds of this invention include, forexample, N-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine,N-ethyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine,N-ethyl-5-(4-fluorophenyl)-6H-1,3,4-thiadiazin-2-amine,N-ethyl-6-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine,5-(4-fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine,6-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine,N,N,6-trimethyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine,5-(2,4-dichlorophenyl)-N,N-dimethyl-6H-1,3,4-thiadiazin-2-amine,5-(2,4-dichlorophenyl)-N-(1-methylethyl)-6H-1,3,4-thiadiazin-2-amine,5-(2,4-dichlorophenyl)-N-(1-propyl)-6H-1,3,4-thiadiazin-2-amine,5-(4-chlorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine,5-(2-fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine,5-(2,4-difluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine,5-(2,4-dibromophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine andN-methyl-5-(2-nitrophenyl)-6H-1,3,4-thiadiazin-2-amine,5-(2,4-dichlorophenyl)-N-2-propenyl-6H-1,3,4-thiadiazin-2-amine and theacid addition salts, e.g., the monohydrochloride, of each.

The compounds of this invention are useful as sedatives. These compoundscan be administered to warm-blooded animals, mammals, rats, mice, dogs,cats, horses, pigs, cows, sheep, and humans. As used herein, the term"patient" is intended to mean the animal or mammal being treated.

The sedative-inducing activity of the compounds employed in the methodof this invention may be illustrated by their effectiveness in standardpharmacological screening tests, e.g., by demonstrating an increase inthe number of mice in a test group who take the side position uponadministration.

The compounds employed in the process of this invention can beadministered orally or parenterally either alone or in the form of apharmaceutical preparation. Pharmaceutical preparations containingconventional pharmaceutical carriers and as active ingredients compoundsof this invention can be employed in unit dosage forms such as solids,for example, tablets, capsules, and pills, or liquid solutions,suspensions, or emulsions for oral and parenteral administration. Thedosage unit administered can be any sedation-inducing effective amount.The quantity of compound administered can vary over a wide range toprovide from about 30 to about 50 mg/kg of body weight of the patientper day, to achieve the desired effect. Unit doses can contain about5-500 mg of a compound of Formula I and may be administered, forexample, from 1 to 4 times daily.

The compounds of Formula I are prepared by reacting a phenacyl halide ofthe formula ##STR3## wherein X is Cl or Br, with a 4-substitutedthiosemicarbazide of the formula ##STR4## wherein R, R₁, R₂ and R₃ areas hereinbefore defined. The reaction is generally conducted in thepresence of a solvent, e.g., a lower alkanol, such as, methanol,ethanol, isopropanol, n-propanol, n-butanol and the like, preferablymethanol. The reaction time may vary from about 15 minutes to about 1hour, preferably about 30 minutes, depending upon the reactants, thesolvent and the reaction temperature which may vary from about 60° C. toabout 80° C., preferably around 65° C. The product is generallyworked-up by permitting the reaction mixture to cool and thenconcentrating it in vacuo. The resultant residue is recrystallized froman appropriate solvent, e.g., a mixture of a lower alkanol with, e.g.,acetone, butanone of ethylacetate, e.g., methanol/acetone ormethanol/ethylacetate, producing the compound of Formula I as itshydrohalide salt. Treatment with base produces a compound of Formula I.

Both the phenacyl halide and the 4-substituted thiosemicarbazide whichare employed as starting materials in the preparation of the compoundsof Formula I are either commercially available or, when unavailable, arevery readily preparable by standard chemical reactions which arewell-known to those of ordinary skill in the art. For example, thephenacyl halides may be prepared by halogenating the correspondingmethyl (optionally-substituted)phenyl ketone using a sulfuryl halide,e.g., sulfuryl chloride, e.g., in acetic acid, e.g., to prepare thecorresponding phenacyl chloride; or by reacting the correspondingoptionally substituted benzene with a haloacetyl halide, e.g.,chloroacetyl chloride via a Friedel Crafts reaction using an aluminumtrichloride catalyst, e.g., to prepare the corresponding phenacylchloride. The 4-substituted thiosemicarbazides may be prepared byconventionally reacting the appropriate substituted isothiocyanate withhydrazine in the presence, e.g., of diethyl ether.

EXAMPLES

The following examples are illustrative of the invention.

EXAMPLE 1 N-Methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydrochloride

5.25 g (0.05 mole) of 4-methyl-thiosemicarbazide and 7.73 g (0.05 mole)of phenacyl chloride are heated and stirred at reflux (65° C.) in 200 mlof methanol for 30 minutes. At this time, the solvent is removed invacuo. The residue is dissolved in methanol, warmed and then dilutedwith acetone. Subsequently, it is concentrated to a volume ofapproximately 200 ml. After standing for about 2 days, 8.33 g ofN-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydrochloride aredeposited. m.p. 176°-178° C.

EXAMPLE 2 N-Ethyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydrochloride

8.35 g (0.05 mole) of 4-ethyl-thiosemicarbazide and 9.95 g (0.05 mole)of phenacyl bromide are heated and stirred at reflux (65° C.) in 300 mlof methanol for 30 minutes. The solvent is removed in vacuo and theresidue is recrystallized from methanol/acetone affording 8.2 g ofN-ethyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydrochloride. m.p.169°-170.5° C. The product is then dried under high vacuum at 65° C.

EXAMPLE 3 N-Ethyl-5-(4-fluorophenyl)-6H-1,3,4-thiadiazin-2-aminehydrochloride

11.19 g (0.067 mole) of 4-ethyl-thiosemicarbazide and 17.6 g (0.1 mole)of (4-fluorophen)acyl chloride are heated and stirred at reflux (65° C.)in 400 ml of methanol for 30 minutes in a 1 liter round bottom flaskequipped with a magnetic steering bar and a condenser protected by aCaCl₂ drying tube. The solution is allowed to cool to room temperatureand is then concentrated. The residue is recrystallized frommethanol/butanone, yielding 21.0 g (75.5%) ofN-ethyl-5-(4-fluorophenyl)-6H-1,3,4-thiadiazin-2-amine hydrochloride.m.p. 192°-193° C. The solid is then dried under high vacuum at 65° C.overnight.

EXAMPLE 4 N-Ethyl-6-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-aminehydrobromide

0.05 mole of α-methyl-phenacyl bromide and 0.05 mole of4-ethyl-thiosemicarbazide are reacted using the procedure of EXAMPLE 1to prepare 8.0 g ofN-ethyl-6-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine-hydrobromide. m.p.174°-175° C. After recrystallization from methanol/ethyl acetate, theproduct is dried at 65° C. under high vacuum.

EXAMPLE 5 5-(4-Fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-aminehydrochloride

8.63 g of (4-fluorophen)acyl chloride and 4.66 g of4-methylthiosemicarbazide are reacted using the conditions of EXAMPLE 1.The resultant product is recrystallized from methanol/ethyl acetateyielding 5.6 g of5-(4-fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine hydrochloride.m.p. 139°-141° C. The product compound is dried under high vacuum at 65°C.

EXAMPLE 6 6-Methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydrobromide

0.05 mole of α-methyl-phenacyl bromide and 0.05 mole ofthiosemicarbazide are heated and stirred at reflux (65° C.) in 200 ml ofmethanol for 30 minutes. The yellowish solution is concentrated in vacuoto produce a yellow solid. The solid is dissolved in methanol, dilutedwith ethyl acetate and then heated until crystallization ensues. Theresultant solid is filtered yielding6-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydrobromide. m.p.191°-192° C. The product is then dried at 65° C. under high vacuum.

EXAMPLE 7 N,N-6-Trimethyl-5-phenyl-6H-1,3,4-thiadiazin-2-aminehydrobromide 5.82 g (0.027 mole) of α-methyl-phenacyl bromide and 3.25 g(0.027 mole) of 4,4-dimethyl-thiosemicarbazide are heated and stirred atreflux (78.5° C.) in 200 ml of ethanol for 30 minutes. The solvent isremoved in vacuo. The residual oil is dissolved in methanol/ethylacetate and concentrated until a reddish colored gum precipitates.Refrigeration of the solution produces yellow crystals. This product isrecrystallized from ethanol/butanone producing yellow crystals ofN,N,6-trimethyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydrobromide. m.p.177°-179° C. The product is dried over methanol under high vacuum.EXAMPLE 85-(2,4-Dichlorophenyl)-N,N-dimethyl-6H-1,3,4-thiadiazin-2-aminemonohydrochloride

4.16 g (0.035 mole) of 4,4-dimethyl-thiosemicarbazide and 7.82 g (0.035mole) of (2,4-dichlorophen)acyl chloride are reacted using theconditions of EXAMPLE 1. The resultant product is dissolved in ethylacetate to produce fluffy yellow needles. These are recrystallized frommethanol/ethylacetate and dried under high vacuum to produce5-(2,4-dichlorophenyl)-N,N-dimethyl-6H-1,3,4-thiadiazin-2-aminemonohydrochloride. m.p. 219°-222° C.

EXAMPLE 95-(2,4-Dichlorophenyl)-N-(1-methylethyl)-6H-1,3,4-thiadiazin-2-aminemonohydrochloride

3.99 g (0.03 mole) of 4-isopropyl-thiosemicarbazide and 6.70 g (0.03mole) of (2,4-dichlorophen)acyl chloride are reacted using theconditions of EXAMPLE 1 except only 150 ml of the methanol solvent areemployed. The product is recrystallized from methanol/ethyl acetatetwice, yielding5-(2,4-dichlorophenyl)-N-(1-methylethyl)-6H-1,3,4-thiadiazin-2-aminemonohydrochloride. m.p. 207°-208° C.

EXAMPLE 10 5-(4-Chlorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-aminemonohydrobromide

5.83 g (0.025 mole) of (4-chlorophen)acyl bromide and 2.63 g of4-methyl-thiosemicarbazide are reacted under the conditions of EXAMPLE 1except that only 150 ml of the solvent methanol are employed. Afterconcentration of the methanol solvent in vacuo, the residue isrecrystallized from methanol/ethyl acetate. A second suchrecrystallization yields5-(4-chlorophenyl-N-methyl-6H-1,3,4-thiadiazin-2-amine monohydrobromide.m.p. 179°-180° C.

EXAMPLE 11 5-(2-Fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-aminemonohydrochloride

8.62 g of (2-fluorophen)acyl chloride and 5.22 g of4-methylthiosemicarbazide are reacted in accordance with the conditionsof EXAMPLE 1 except that only 150 ml of the methanol solvent areemployed. After recrystallization from methanol/ethyl acetate, 6.7 g of5-(2-fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-aminemonohydrochloride are obtained. m.p. 183°-184° C.

EXAMPLE 12 5-(2,4-Difluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-aminemonohydrochloride

7.62 g (0.04 mole) of (2,4-difluorophen)acyl chloride and 4.20 g (0.04mole) of 4-methyl-thiosemicarbazide are heated with stirring underreflux (78.5° C.) in 200 ml of ethanol. The solvent is concentrated invacuo and the residue is recrystallized from methanol/ethyl acetate twotimes. It is then recrystallized from methanol/butanone, producing5-(2,4-difluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-aminemonohydrochloride. m.p. 182°-184° C. The product is dried at 65° C.under high vacuum.

EXAMPLE 13 5-(2,4-Dibromophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-aminemonohydrochloride

2.1 g (0.0077 mole) of (2,4-dibromophen)acyl chloride and 0.81 g (0.0077mole) of 4-methyl-thiosemicarbazide are heated and stirred at reflux in150 ml of methanol for 35 minutes. After concentration of the solvent, ayellow foamy gum is produced. The gum is dissolved in methylenechloride/methanol/ethyl acetate. The solvent is concentrated, producinga gum which, upon scratching and cooling, slowly becomes a solid. Thesolid is filtered and dried at 78° C. under high vacuum, yielding5-(2,4-dibromophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-aminemonohydrochloride. m.p. 184°-186° C.

EXAMPLE 14 N-Methyl-5-(2-nitrophenyl)-6H-1,3,4-thiadiazin-2-aminemonohydrobromide

9.2 g (0.0375 mole) of (2-nitrophen)acyl bromide and 3.5 g (0.03 mole)of 4-methyl-thiosemicarbazide are heated and stirred at reflux in 250 mlof methanol. The solution is concentrated and a solid crystallizes out.The solid is recrystallized from methanol/ethanol and filtered. Theresultant powder is recrystallized from methanol/ethyl acetate toproduce 3.8 g of N-methyl-5-(2-nitrophenyl)-6H-1,3,4-thiadiazin-2-aminemonohydrobromide. m.p. 229°-230° C.

EXAMPLE 155-(2,4-Dichlorophenyl)-N-2-propenyl-6H-1,3,4-thiadiazin-2-aminemonohydrochloride

3.93 g (0.03 mole) of 4-allyl-thiosemicarbazide and 7.00 g (0.03 mole)of (2,4-dichlorophen)acyl chloride and reacted in accordance with theconditions of EXAMPLE 1. Recrystallization from methanol/methyl acetateproduces 8 g of5-(2,4-D-dichlorophenyl)-N-2-propenyl-6H-1,3,4-thiadiazin-2-amine m.p.188°-189° C.

EXAMPLE 165-(2,4-dichlorophenyl)-N-(1-propyl)-6H-1,3,4-thiadiazin-2-aminemonohydrochloride

Analogously to EXAMPLE 1, 3.99 g (0.03 mole) of4-n-propyl-thiosemicarbazide and 6.70 g (0.03 mole) of(2,4-dichlorophen)acyl chloride are reacted. After recrystallizationfrom methanol/methyl acetate, 6.4 g of5-(2,4-dichlorophenyl)-N-(1-propyl)-6H-1,3,4-thiadiazin-2-amine areobtained. m.p. 184°-185° C.

EXAMPLE 17

An illustrative composition for tablets is as follows:

    ______________________________________                                                               Per Tablet                                             ______________________________________                                        (a)   5-(2,4-Dichlorophenyl)-N,N-dimethyl-                                          6H-1,3,4-thiadiazin-2-amine mono-                                             hydrochloride          100.0 mg                                         (b)   wheat starch           15.0 mg                                          (c)   lactose                33.5 mg                                          (d)   magnesium stearate     1.5 mg                                           ______________________________________                                    

A portion of the wheat starch is used to make a granulated starch pastewhich together with the remainder of the wheat starch and the lactose isgranulated, screened and mixed with the active ingredient (a), and themagnesium stearate. The mixture is compressed into tablets weighing 150mg each.

EXAMPLE 18

An illustrative composition for a parenteral injection is the followingwherein the quantities are on a weight to volume basis.

    ______________________________________                                                                Amount                                                ______________________________________                                        (a)   5-(2,4-Dichlorophenyl)-N,N-dimethyl-                                          6H-1,3,4-thiadiazin-2-amine mono-                                             hydrochloride           100.0 g                                         (b)   sodium chloride         q.s.                                            (c)   water for injection to make                                                                           20 ml                                           ______________________________________                                    

The composition is prepared by dissolving the active ingredient (a) andsufficient sodium chloride in water for injection to render the solutionisotonic. The composition may be dispensed in a single ampoulecontaining 100 mg of the active ingredient for multiple dosage or in 20ampoules for single dosage.

EXAMPLE 19

An illustrative composition for hard gelatin capsules is as follows:

    ______________________________________                                                               Amount                                                 ______________________________________                                        (a)   5-(2,4-Dichlorophenyl)-N,N-dimethyl-                                          6H-1,3,4-thiadiazin-2-amine mono-                                             hydrochloride          200.0 mg                                         (b)   talc                   35.0 mg                                          ______________________________________                                    

The composition is prepared by passing the dry powders of (a) and (b)through a fine mesh screen and mixing them well. The powder is thenfilled into No. 0 hard gelatin capsules at a net fill of 235 mg percapsule.

EXAMPLE 20

An illustrative composition for pills is the following:

    ______________________________________                                                               Per Pill                                               ______________________________________                                        (a)  5-(2,4-Dichloropheny)-N,N-dimethyl-                                           6H-1,3,4-thiadiazin-2-amine mono-                                             hydrochloride           200 mg                                           (b)  corn starch             130 mg                                           (c)  liquid glucose           20 ml                                           ______________________________________                                    

The pills are prepared by blending the active ingredient (a) and thecorn starch and then adding the liquid glucose with thorough kneading toform a plastic mass from which the pills are cut and formed.

Treatment of each of the compounds of EXAMPLES 1-16 with base, e.g.,aqueous NaOH, produces the corresponding free amine of Formula 1 whichafter isolation and purification in the conventional manner, can besubstituted for the hydrochloride salt employed in each of EXAMPLES17-20.

EXAMPLE 21

The compounds of the preceding examples can be administered as asedative for the treatment of, e.g., insomnia, preoperative, obstetricaland daytime sedation.

Sedation is inducible in mice under conditions comparable to thatemployed by administration of diazepam (Valium) parenterally (i.v.). Forexample, the compound of Example 1 or 3 has about 1/7 the potency ofdiazepam, whereas the compound of Example 8 has about 1/4 the potency ofdiazepam, under similar conditions of parenteral administration.Therefore, the compound under consideration will be administered tohumans for the same indications and under the same dosage conditions(adjusted for differential potency) as those seen in mice for diazepam.For example, the compound of Example 8 can be administered orally indoses of 1050 mg., 2 to 4 times daily, for beneficial sedative effect.

I claim:
 1. A method of inducing sedation in a patient which comprisesadministering to a patient in which sedation is desired an amounteffective for inducing sedation of a compound of the formula ##STR5##wherein R is H, or C₁₋₅ or 7 -straight or branched chain alkyl;R₁ is H,C₁₋₅ or 7 -straight or branched chain alkyl or allyl; R₂ is phenyl orphenyl substituted with F, Cl, Br, No₂, C₁₋₅ straight or branched chainalkyl, C₁₋₅ straight or branched chain alkoxy, 2,4-di-Cl, 2,4-di-F,2,4-di-Br with the proviso that when the phenyl group is monosubstitutedwith F, the F atom is not in the o-position; and R₃ is H or C₁₋₅straight or branched chain alkyl, with the proviso that when R₃ isstraight or branched chain alkyl, R₂ is unsubstituted phenyl; or apharmaceutically acceptable acid addition salt thereof.
 2. The method ofclaim 1, wherein the amount of the active compound which is administeredis 30-50 mg/kg of patient body weight per day.
 3. The method of claim 1,wherein the compound administered is one wherein R₂ is2,4-dichlorophenyl.
 4. The method of claim 3, wherein the compoundadministered is one wherein R₁ is C₁₋₅ straight or branched chain alkylor allyl.
 5. The method of claim 1, wherein the compound administered is5-(2,4-dichlorophenyl)-N,N-dimethyl-6H-1,3,4-thiadiazin-2-aminemonohydrochloride.
 6. The method of claim 1, wherein the compoundadministered is5-(2,4-dichlorophenyl)-N-(1-propyl)-6H-1,3,4-thiadiazin-2-aminemonohydrochloride.
 7. The method of claim 1, wherein the compoundadministered is5-(2,4-dichlorophenyl)-N-2-propenyl-6H-1,3,4-thiadiazin-2-amine.